Repression of GSK3 restores NK cell cytotoxicity in AML patients

Nat Commun. 2016 Apr 4:7:11154. doi: 10.1038/ncomms11154.

Abstract

Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / chemistry
  • Aminophenols / pharmacology
  • Animals
  • Cellular Microenvironment
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Immunotherapy
  • Intercellular Adhesion Molecule-1 / metabolism
  • Killer Cells, Natural / immunology*
  • Leukemia, Myeloid, Acute / immunology*
  • Maleimides / chemistry
  • Maleimides / pharmacology
  • Mice
  • NF-kappa B / metabolism
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology
  • Tumor Necrosis Factor-alpha

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • 3-(9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro(1,4)diazepino(6,7,1-hi)indol-7-yl)-4-imidazo(1,2-a)pyridin-3-yl-1H-pyrrole-2,5-dione
  • Aminophenols
  • Heterocyclic Compounds, 3-Ring
  • Maleimides
  • NF-kappa B
  • Thiadiazoles
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • tideglusib